Amyloid-beta (A?) plaques and tau-containing neurofibrillary tangles (NFTs) are the two pathological hallmarks of Alzheimer's disease. A number of studies suggest that A? works upstream of tau to promote neurological dysfunction and neuronal death in Alzheimer's disease. Most importantly, A?-induced neurotoxicity and cognition deficits are significantly ameliorated by reductions in tau in several in vivo models. However, the mechanism by which A? promotes tau neurotoxicity remains a major unanswered question in the field of Alzheimer's disease research. To address this important question using an unbiased forward genetic approach, we have developed a model of A?-controlled tau neurotoxicity in the simple model organism Drosophila. We have used a genetic screen to identify candidate genes that when decreased in expression substantially alter A?-induced tau toxicity. I will now build on these preliminary results to validate and examine mechanistically the influence of candidate proteins and pathways on A?-induced neurotoxicity. Since A? toxicity in flies, as in mammalian systems, is transduced substantially through endogenous tau, I will use state-of-the-art genome editing with CRISPR/CAS to produce a null mutation in the fly tau gene. A null mutation in tau will allow us to assay the dependence of our modifier pathways unequivocally on tau. Further, given the reduced redundancy of the Drosophila genome, analysis of tau null flies may provide important insights into the normal role of tau, an important and understudied area of cell biology and disease pathobiology. I will use a variety of experimental approaches in my studies, including genetics, molecular biology, cell biology, neuropathology and biochemistry. Collectively, my studies will define novel connections between A? and tau, and thereby significantly advance our understanding of the mechanisms regulating interactions of these two hallmark Alzheimer's disease related proteins. In concert with these important scientific goals, the research plan will provide me with strong training in a complementary group of disciplines critical for my long-term success as an independent investigator.